In this review, we have primarily restricted ourselves to tumour-targeted nanomedicines designed for the improved delivery of already established, low-molecular-weight chemotherapeutics. Many of the new drugs arising from advances in biotechnology, however, are macromolecules, such as proteins and nucleic acids. The clinical development of these challenging and often fragile molecules will likely also profit substantially from the attributes of targeted nanomedicines, providing these complex molecules, for example, with protection against degradation and elimination, and with improved access to target cells and tissues.
In the document ‘Forward Look on Nanomedicine', the European Science Foundation included in their definition of the discipline of nanomedicine not only the use of nanometer-sized materials for the treatment but also for the diagnosis of diseases. Regarding the latter aspect, the development of high-resolution imaging techniques (such as, MRI and PET) for the rapid, noninvasive monitoring of the in vivo fate and performance of targeted nanomedicines is currently receiving intense attention, and will certainly facilitate the implementation of imaging-guided drug delivery to promote the optimal use of (tumour-) targeted nanomedicines.
Additional areas likely to receive considerable attention in the years to come are:
- the design of systems that are able to respond to externally applied stimuli, such as, hyperthermia, ultrasound, light and magnetic fields, and that can be triggered to release their contents (like Thermodox; );
- the targeting of agents other than conventional chemotherapeutic drugs to tumours, such as, anti-inflammatory agents (e.g., corticosteroids) to inhibit tumour-associated inflammation (Schiffelers et al, 2006), and siRNA to reduce the expression of proteins essential for tumour progression (Schiffelers et al, 2004);
- the development of systems that are able to simultaneously deliver multiple therapeutic agents to tumours, such as temporally targeted ‘nanocells', which first release the anti-angiogenic agent combrestatin and subsequently the chemotherapeutic agent doxorubicin (Sengupta et al, 2005);
- the translation of the experience gained in oncology into applications for improving the treatment of other diseases, such as rheumatoid arthritis, Crohn's disease, autoimmune diseases and infections, which are all highly amenable to (EPR-mediated) drug targeting (Schiffelers et al, 2006); and
- the establishment of treatment regimens in which tumour-targeted nanomedicines are combined with other clinically relevant treatment modalities, such as with surgery, with radiotherapy and with (standard) chemotherapy.
For obvious reasons, the latter of the above strategies has thus far received the most clinical attention. During surgery, for instance, sustained-release delivery devices, such as Gliadel (i.e., carmustine-containing polymeric wafers), can be implanted into those parts of glioblastoma lesions that cannot be removed surgically (see ). In addition to this, also systems originally intended for systemic administration, such as polymers and liposomes, have been shown to hold potential for such local interventions (Lammers et al, 2006
). Regarding radiotherapy, preclinical and early clinical evidence suggest that tumour-targeted nanomedicines and radiotherapy interact synergistically, with radiotherapy improving the tumour accumulation of the delivery systems, and with the delivery systems improving the interaction between radiotherapy and chemotherapy (Li et al, 2000
; Dipetrillo et al, 2006
; Lammers et al, 2008
). And regarding chemotherapy, both Myocet and Caelyx have been successfully included in several different combination chemotherapy trials (Hofheinz et al, 2005
), and also for Abraxane initial results obtained in combination regimens are promising. Combinations of molecularly targeted therapeutics with tumour-targeted therapeutics have also already been evaluated, showing, for example, that the combination of Avastin (Bevacizumab) with Abraxane produced an overall response rate of almost 50% in heavily pretreated breast cancer patients (Link et al, 2007
Since the approval, in 1995, of the first tumour-targeted anticancer nanomedicine (Caelyx/Doxil, i.e., stealth liposomal doxorubicin), targeted nanomedicines have become an established addition to the anticancer drug arsenal, with several formulations presently on the market. A major limitation impeding the entry of targeted nanomedicines onto the market is that new concepts and innovative research ideas within academia are not being developed and exploited in collaboration with the pharmaceutical industry. An integrated ‘bench-to-clinic' approach, realised within a structural collaboration between industry and academia, would strongly stimulate the progression of tumour-targeted nanomedicines towards clinical application.